Signal Transducer and Activator of Transcription 3 Activation Promotes Invasive Growth of Colon Carcinomas through Matrix Metal loproteinase Induction

Abstract

Signal transducer and activator of transcription 3 (STAT3) is aberrantly activated in colorectal carcinomas (CRCs). Here, we define the relationship between STAT3 function and the malignant properties of colon carcinoma cells. Elevated activation of STAT3 enhances invasive growth of the CRC cell lines. To address mechanisms through which STAT3 influences invasiveness, the protease mRNA expression pattern of CRC biopsies was analyzed and correlated with the STAT3 activity status. These studies revealed a striking coincidence of STAT3 activation and strong expression of matrix metalloproteinases MMP-1, -3, -7, and -9. Immunohistological examination of CRC tumor specimens showed a clear colocalization of MMP-1 and activated STAT3. Experimentally induced STAT3 activity in CRC cell lines enhanced both the level of MMP-1 mRNA and secreted MMP-1 enzymatic activity. A direct connection of STAT3 activity and transcription from the MMP-1 promoter was shown by reporter gene experiments. Moreover, high-affinity binding of STAT3 to STAT recognition elements in both the MMP-1 and MMP-3 promoter was demonstrated. Xenograft tumors arising from implantation of CRC cells into nude mice showed simultaneous appearance and colocalization of p-Y-STAT3 and MMP-1 expression. Our results link aberrant activity of STAT3 in CRC to malignant tumor progression through upregulated expression of MMPs.

Protein Expression of STAT3, pSTAT3, MMP-7 and VEGF in Colorectal Adenocarcinoma: An Immunohistochemical Study

“…Recently, Cascio and co-investigators supported this evidence in colon cancer cells by demonstrating the binding of STAT3 to the promoter of VEGF [47]. Elevated levels of MMP-7 mRNA was detected in colorectal tumor tissues with activated form of STAT3 [3]. In addition to MMP-7, aberrant activity of STAT3 could be a major factor of local tumor progression and metastasis of colorectal cancer through upregulation of other MMPs including MMP-1, MMP-3 and MMP-9 [3].…”

“…Elevated levels of MMP-7 mRNA was detected in colorectal tumor tissues with activated form of STAT3 [3]. In addition to MMP-7, aberrant activity of STAT3 could be a major factor of local tumor progression and metastasis of colorectal cancer through upregulation of other MMPs including MMP-1, MMP-3 and MMP-9 [3]. This could also explain the reason that we noted pSTAT3 was significantly associated with MMP-7 but STAT3 showed marginal association with MMP-7.…”

The tumor suppressor geneARHI(DIRAS3)inhibits ovarian cancer cell migration through multiple mechanisms

“…The critical target genes transcriptionally regulated by STAT3 include integrin, FN and MMP-3. 36,58 Thus, the loss of ARHI-induced blockade of STAT3 signaling may be one critical mechanism regulating motility and invasion, not only in ovarian cancer, but in breast, lung, prostate and pancreatic cancer where ARHI is also downregulated. The engagement of integrin with extracellular matrix proteins results in the regulation of the small GTPase.…”

Therapeutic Efficacy of CEP-33779, a Novel Selective JAK2 Inhibitor, in a Mouse Model of Colitis-Induced Colorectal Cancer

“…Patients with colorectal cancer have often elevated levels of IL-6 in the serum (12), and constitutively activated STAT3, which is expressed in the majority of colorectal tumors (13,14) is associated with a significantly higher mortality. Constitutive STAT3 activation in colorectal cancer-derived cell lines promoted proliferation and invasiveness of tumor cells in culture (15) and growth of tumor xenografts (13) in an IL-6-dependent manner (16).…”